Structural and functional imaging studies have suggested a neurocircuitry of mood disorders that involves a limbicthalamic-cortical circuit (amygdala, thalamus, prefrontal cortex) and a limbic-striatal-pallidal-thalamic-cortical circuit. Abnormalities in a component of these circuits may affect the regulation of mood. Serotonin has been implicated in the pathophysiology of depression. Reports of fewer platelet serotonin transporters in major depression have rarely been extended to postmortem brain studies and neuroreceptor imaging studies in vivo. Serotonin transporter binding in the brainstem of depressed patients measured by SPECT is reportedly lower. ["C]McN5652 is a PET radioligand with high affinity for the serotonin transporter. Our group has developed kinetic modeling methods with this ligand that allow quantification of the serotonin transporter in subcortical and to a lesser extent in some cortical structures. We propose an in vivo study of the neurocircuitry of the serotonergic system in major depression. We predict that transporter binding will be decreased in depressed subjects in the midbrain, thalamus, putamen, hippocampus, and amygdala. Symptoms of depression have been correlated to serotonergic measures, including suicidal ideation, psychomotor retardation, and anxiety. We will correlate these measures of psychopathology with ["C]McN5652 binding. Correlations will help refine the neurocircuitry model of depression. Several lines of evidence suggest that serotonin dysfunction in depression may be a trait marker. Consequently, we will study both currently depressed (n=40) and remitted depressed subjects (N=20) while off medication, and compare both groups to healthy volunteers (N=20). We predict remitted depressed will not differ from currently depressed subjects. These results will greatly enhance our knowledge of the pathophysiology of major depression and help in our diagnosis, treatment, and design of future studies. This application for a Mentored Clinical Scientist Development Award has been submitted with the goal of supporting the development of the applicant's career as a psychiatric researcher. This research plan is intended to build on the candidate's prior work with neuroreceptor imaging in mood disorders. This application delineates plans for training and mentoring in the areas of the neurobiology of depression, cell and molecular physiology, pharmacology, neuroanatomy, statistical analysis, clinical diagnosis and ratings, teaching, brain imaging, and mathematical modeling necessary to enable the applicant to pursue an independent career of scientific inquiry in psychiatry. These goals will be met by a combination of didactic I course work and supervision.